ATP-gated cation channel (purinoceptor or ATP-neuroreceptor). His33 and Ser345 are proximal to each other across an intra-subunit interface, and the relative movement between the two TMSs is likely important for transmitting the action of ATP binding to the opening of the
channel (Liang et al. 2013). Two processes contribute
to receptor desensitization, one, bath calcium-independent and the other, bath calcium-dependent, the latter being more important (Coddou et al. 2015). ATP dissociation causes reduction in outer pore expansion compared to the ATP-bound state. Moreover, the inner and outer ends of adjacent pore-lining helices come closer during
opening, likely through a hinge-bending motion (Habermacher et al. 2016).

ATP-gated NaCl-regulated nonselective cation (Na+, K+ and Ca2+) channel, the P2X purinoreceptor 7 (expands to accommodate large molecules such as NAD, N-methyl-D-glucamine and triethyl ammonium) (Li et al., 2005; Lu et al., 2007). Plays a role in changing pain thresholds. A region called ADSEG in all P2X receptors is located in the M2 domain which aligns with TMS 5 in VIC K+ channels (1.A.1). ADSEG from P2X(7)R forms cation-selective channels in artificial lipid bilayers and biological membranes similar to those of the full length protein (de Souza et al., 2011). Regulated by calmodulin (Roger et al., 2008). P2XRs allow direct permeation of nanometer-sized dyes (Browne et al. 2013). Macrophage P2X7 receptors are modulated in response to infection with Leishmania amazonensis so that they become more permeable to anions and less permeable to cations (Marques-da-Silva et al. 2011). Residues involved in pore conductivity and agonist sensitivity have been identified (Jindrichova et al. 2015) as have residues involved in channel activation (Caseley et al. 2016). The channel opening extends from the pre-TMS 2 region through the outer half of the trihelical TMS 2 channel; the gate and the selectivity filter have been identified (Pippel et al. 2017). The purinergic receptors, P2RX4 and P2RX7, when mutated, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017). P2X7 may serve as a receptor for the regulation of annexin secretion during macrophage polarization (de Torre-Minguela et al. 2016). These receptors can reduce salivary gland inflammation (Khalafalla et al. 2017). The P2X7 receptor forms ion channels dependent on lipids but independently of its cytoplasmic domain (Karasawa et al. 2017). A truncated naturally occurring variant of P2X7, P2X7-j of 258 aas, lacked the entire intracellular carboxyl terminus, the second TMS, and the distal third of the extracellular loop of the full-length P2X7 receptor. P2X7-j was expressed in the plasma membrane; it failed to form pores and mediate apoptosis (Feng et al. 2006). P2X7-j formed heterooligomers with and blocked P2X7-mediated channel formation.

P2X(4) of the zebrafish (3-d structure known in its closed, resting state) (Kawate et al., 2009). Shift of L340 packing between different sites may alter the side-chain orientation that
frees or occludes the pore. L340, A344 and A347 may also gate the pore by a expansion-
contraction mechanism (Li 2015).

The purinergic receptor, P2X4, is sensitive to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating (Samways et al., 2012). The gating mechanism has been discussed (Du et al., 2012) and considered to be determined by the conformation of the transmembrane domain (Minato et al. 2016; Pierdominici-Sottile et al. 2016). The crystal structure of the ATP-gated P2X(4) ion channel in the closed state has been reported (Kawate et al., 2009). Unobstructed lateral portals are preferentially used as access routes to the pores of P2X receptors (Samways et al., 2011). Activation is ATP-dependent and rapid, but desensitization occurs within seconds and is ATP-independent (Stojilkovic et al. 2010). Ectodomain cysteines play roles in agonist binding and channel gating (Rokic et al. 2010). Evermectin has distinct effects on opening and dilation of the channel pore, the first
accounting for increased peak current amplitude, and the latter correlating with changes in the kinetics of receptor deactivation (Zemkova et al. 2014). Conserved amino acids within the regions linking the ectodomain with the pore-forming transmembrane
domain may contribute to signal transduction and channel gating (Gao et al. 2015; Jelínkova et al. 2008). Binding of ATP
produces distortions in the chains that eliminate restrictions on the interchain displacements,
leading to the opening of the pore (Pierdominici-Sottile et al. 2016). The purinergic receptors, P2RX4 and P2RX7, affect susceptibility to multiple sclerosis (MS) (Sadovnick et al. 2017).

ATP-gated P2X3 receptor. Tyr-37 stabilizes desensitized states and restricts calcium permeability (Jindrichova et al., 2011). Exhibits "high affinity desensitization" but slow reactivation from the desensitized state (Giniatullin and Nistri 2013). An
endogenous regulator of P2X3 in bladder is the Pirt protein (TC#8.A.64.1.1) Gao et al. 2015). X-ray crystal structures of the human P2X3 receptor in apo/resting,
agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states have been determined (Mansoor et al. 2016).
The open state structure harbours an intracellular motif termed the 'cytoplasmic cap', which
stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined
cytoplasmic fenestrations for water and ion egress.

The osmoregulatory intracellular P2X receptor, P2XA gated by ATP (present in the osmoreulatory organelle, the contractile vacuole) (Fountain et al., 2007). One of five P2X receptors in D. discoideum is localized to the contractile vacuole with the ligand binding domain facing the lumen. Plays a role in Ca2+ signaling, but also is Cl- permeable. May function in osmoregulation (Ludlow et al., 2009).